• Modulation of Pathophysiological Processes of Autoimmune Arthritis by Indole-3-Acetic acid and Indole-3-Aldehyde

      Langan, David; Meka, Rakeshchandra R.; Moudgil, Kamal (2020-03)
      Rheumatoid arthritis (RA) afflicts 0.5-1% of US adults, making it one of most common autoimmune diseases. Clinical RA is characterized by swelling of the joints of both extremities. Environmental factors, including diet and microbiome dysbiosis, are disease-modifying factors for RA. Indole-3-acetic acid (I3AA) and indole-3-aldehyde (IAld) are derived from both the diet and gut microbiota. We hypothesized that I3AA and IAld, ligands for the aryl hydrocarbon receptor (AhR), regulate critical AhR-dependent arthritisrelated processes, namely production of pro-inflammatory cytokines, angiogenesis (new blood vessel formation), and osteoclastogenesis (bone resorption). We tested this using in vitro models of these 3 processes. Both I3AA and IAld inhibited IL-1β and IL-6 expression (by RT-qPCR), in RAW264.7 (RAW) cells treated with M. tuberculosis H37Ra sonicate (H37Ra) or LPS compared with vehicle control. Additionally, I3AA-treated RAW cells cultured in the presence of receptor activated nuclear-factor kappa beta (RANKL) formed fewer osteoclasts along with reduced expression of tartrate-acid phosphatase (TRAP) and cathepsin-K expression (CatK) (by RTqPCR), compared to vehicle-treated cells; whereas, IAld-treated cells formed more osteoclast along with more TRAP and CatK expression. Human umbilical vein endothelial cell (HUVEC) tube formation (Matrigel assay), indicative of angiogenesis, was inhibited by I3AA, while IAld had minimal or no effect. These preliminary results suggest that I3AA and IAld are capable of modulating key RA-disease processes. We plan to examine the effect of AhR inhibitors on these processes, and to assess whether I3AA and/or IAld can confer protection against arthritis in a rat model of RA.